Basic Statistical Concepts

Chapter 2 Reading
instructions

2.1 Introduction: Not very important

2.2 Uncertainty and probability: Read
2.3 Bias and variability: Read
2.4 Confounding and interaction: Read
2.5 Descriptive and inferential statistics:
Repetition
2.6 Hypothesis testing and p-values: Read
2.7 Clinical significance and clinical equivalence:
Read
2.8 Reproducibility and generalizability: Read

Bias and variability

E
Bias: Systemtic deviation from the true value
Design, Conduct, Analysis, Evaluation

Lots of examples on page 49-5

Bias and variability

Larger study does not decrease bias

Distribution of sample means:

Drog X - Placebo

-10

-7

Drog X - Placebo

-4

n=40

mm Hg

-10

Population mean
bias

= population mean
Drog X - Placebo

-7

-4

n=200

mm Hg

-10

-7

-4

N=2000

mm Hg

Bias and variability

There is a multitude of sources for bias
Publication bias
Selection bias
Exposure bias

Positive results tend to be published while negative of

inconclusive results tend to not to be published
The outcome is correlated with the exposure. As an
example, treatments tends to be prescribed to those
thought to benefit from them. Can be controlled by
randomization
Differences in exposure e.g. compliance to treatment
could be associated with the outcome, e.g. patents
with side effects stops taking their treatment

Detection bias

The outcome is observed with different intensity

depending no the exposure. Can be controlled by
blinding investigators and patients

Analysis bias

Essentially the I error, but also bias caused by model

miss specifications and choice of estimation
technique

Interpretation
bias

Strong preconceived views can influence how

analysis results are interpreted.

Bias and variability

Amount of difference between observations
True biological:

Temporal:

Variation between subject

due to biological factors
(covariates) including the
treatment.
Variation over time (and space)
Often within subjects.

Measurement error: Related to instruments or observers

Design, Conduct, Analysis, Evaluation

Raw Blood pressure data

Placebo
DBP
(mmHg)

Drug X

Baseline

Subset of plotted data

8 weeks

Bias and variability

Y X
Variation
= Explaine + Unexplaine
in
d
d variation
observation
variation
s

Bias and variability

Is there any difference between drug A and drug B?

Drug A
Drug B

Outcome

Bias and variability

Model: Yij i xij ij

Y=B+x
B

Y=A+x

A
x=age

Confounding
Predictors
of
treatment

Confounder
s

Predictors
of outcome

A
Treatment
Treatment
allocation
allocation

Outcome
B

Example
Smoking Cigarettes is not so bad but watch
out for Cigars or Pipes (at least in Canada)
Variable

Non smokers Cigarette

smokers

Mortality rate* 20.2

*) per 1000 person-years %

20.5

Cigar or pipe
smokers
35.5
Cochran, Biometrics 1968

Example

Smoking Cigaretts is not so bad but watch

out for Cigars or Pipes (at least in Canada)
Variable

Non smokers Cigarette

smokers

Cigar or pipe
smokers

Mortality rate* 20.2

20.5

35.5

Average age

50.5

65.9

54.9

*) per 1000 person-years %

Cochran, Biometrics 1968

Example

Smoking Cigaretts is not so bad but watch

out for Cigars or Pipes (at least in Canada)
Variable

Non smokers Cigarette

smokers

Cigar or pipe
smokers

Mortality rate* 20.2

20.5

35.5

Average age

54.9

50.5

65.9

Adjusted
20.2
mortality rate*

26.4

24.0

*) per 1000 person-years %

Cochran, Biometrics 1968

Confounding
The effect of two or more factors can not be separated
Example: Compare survival for
surgery and drug

Survival

Life long treatment with drug

Looks ok

Surgery at time 0
Surgery only if healty enough
but:Patients in the surgery arm may take
drug
Complience in the drug arm May be

Time

Confounding
Can be sometimes be handled in the design
Example: Different effects in males and females
Imbalance between genders affects result
Stratify by gender
A

Gender

R
B
Balance on average

B
A

Always balance

Interaction
The outcome on one variable
depends on the value of another
variable.
Example Interaction between two drugs
A

B
A=AZD1234
Wash
out

R
B

B=AZD1234 +
A

Clarithromycin

Interaction
Example: Drug interaction
Plasma concentration (mol/L)
linear scale

Mean
5

AZD1234

AZD0865 alone

Combination
of clarithromycin
AZD1234
and AZD0865

2
1
0
0

12

16

20

24

Time after dose

AUC AZD1234:

19.75 (mol*h/L)

AUC AZD1234 + Clarithromycin:36.62 (mol*h/L)

Ratio:
0.55 [0.51, 0.61]

Interaction
Example: Treatment by center interaction
Treatment difference in diastolic blood pressure
15
10
5
mmHg

0
-5

10

15

20

25

30

-10
-15
-20
-25
Ordered center number

Average treatment effect: -4.39 [-6.3, -2.4] mmHg

Treatment by center: p=0.01
What can be said about the treatment effect?

Descriptive and inferential

statistics
The presentation of the results from a clinical
trial can be split in three categories:

Descriptive statistics
Inferential statistics
Explorative statistics

Descriptive and inferential

statistics
Descriptive statistics aims to describe various
aspects of the data obtained in the study.
Listings.
Summary statistics (Mean, Standard Deviation).
Graphics.

Descriptive and inferential

statistics
Inferential statistics forms a basis for a
conclusion regarding a prespecified objective
addressing the underlying population.

Confirmatory analysis:
Hypothesis

Results

Conclusion

Descriptive and inferential

statistics
Explorative statistics aims to find interesting
results that
Can be used to formulate new
objectives/hypothesis for further investigation in
future studies.analysis:
Explorative
Results

Hypothesis
Conclusion?

Hypothesis testing, p-values

and confidence intervals
Objectives
Variable
Design
Statistical Model
Null hypothesis

Estimate
p-value
Confidence interval

Results
Interpretation

Hypothesis testing, pvalues

X
,

R
Statistical model: Observations 1
n

from a class of distribution functions

P :

Hypothesis test: Set up a null hypothesis:

H0: 0

and an alternative H1: 1

Reject H0 if X S c R n

P X S c | 0

Rejection region

Significance level

p-value:The smallest significance level for

which the null hypothesis can be
rejected.

Confidence intervals
Let X, *

1 if H 0 : * rejected
0 if H 0 : not rejected
*

(critical function)

Confidence set:C X : X, 0
The set of parameter values correponding to
hypotheses that can not be rejected.

C X
A confidence set is a random subset
covering the true parameter value with
1 at least
probability
.

Example
Objective: To compare sitting diastolic blood pressure (DBP) lowering effect
of hypersartan 16 mg with that of hypersartan 8 mg

Variable: The change from baseline to end of study in sitting DBP

(sitting SBP) will be described with an ANCOVA model,
with treatment as a factor and baseline blood pressure
as a covariate
treatment effect
yij = + i + (xij - x) + ij i = 1,2,3
Model:
{16 mg, 8 mg, 4 mg}

4
Parameter space:
R

1 2 3 0

R
Null hypoteses (subsets of
H01: 1 = 2 (DBP)
H02: 1 = 2 (SBP)
H03: 2 = 3 (DBP)
H04: 2 = 3 (SBP)

):

Example contined
Hypothesis

Variable

1: 16 mg vs 8 mg

Sitting
DBP

2: 16 mg vs 8 mg
3: 8 mg vs 4 mg
4 : 8 mg vs 4 mg

This is a t-test

CI (95%)

p-value

-3.7 mmHg

[-4.6, -2.8]

<0.001

Sitting
SBP

-7.6 mmHg

[-9.2, -6.1]

<0.001

Sitting
DBP

-0.9 mmHg

[-1.8, 0.0]

0.055

-2.1 mmHg

[-3.6, -0.6]

0.005

Sitting
SBP the
where

Rejection region:X : T
-c

LS Mean

test statistic follows a t-distribution

T X

P-value: The null hypothesis can pre rejected

at0.001

-4.6

-2.8

1 2

P-value says nothing about

the size of the effect!
Example: Simulated data. The difference between treatment
and placebo is 0.3 mmHg

No. of patients per group

Estimation of effect

p-value

10

1.94 mmHg

0.376

100

-0.65 mmHg

0.378

1000

0.33 mmHg

0.129

10000

0.28 mmHg

<0.0001

100000

0.30 mmHg

<0.0001

A statistical significant difference does NOT

need to be clinically relevant!

Statistical and clinical

significance
Is there any difference
between the evaluated
treatments?
Clinical significance:
Does this difference have
any meaning for the
patients?
Is
Health ecominical relevance:there any economical
benefit for the society in
using the new treatment?
Statistical significance:

Statistical and clinical

significance
A study comparing gastroprazole 40 mg and mygloprazole
30 mg with respect to healing of erosived eosophagitis after
8 weeks treatment.

Drug

Healing rate

gastroprazole 40
mg

87.6%

mygloprazole 30
mg

84.2%

Cochran Mantel Haenszel p-value = 0.0007

Statistically significant!
Clinically significant?
Health economically relevant?